TOKYO--(BUSINESS WIRE)--Jan 24, 2011 - Kowa Company, Ltd.
announced today that the results of subgroup analyses in the
peretinoin (generic name; code, NIK-333) Phase II/III clinical
trial, which evaluated its suppressive efficacy on recurrence of
hepatocellular carcinoma (HCC), were presented at the General
Poster Session of American Society of Clinical Oncology
Gastrointestinal Cancers Symposium 2011 (ASCO-GI 2011) on January
21, 2011 in San Francisco, USA (Abstract number #165).

The analyses were performed in two subgroups (patients with mild
(Child-Pugh A*) liver impairment or patients with Child-Pugh A
impairment with a major tumor diameter of less than 20mm prior to
the curative therapy).

In these subgroups, peretinoin 600mg/day showed a significantly
greater reduction in the risk of HCC recurrence or death (the
primary endpoint) compared to placebo. These results were better
than in the study as a whole and appear to indicate subgroups of
patients who may benefit from peretinoin therapy. The observation
gives a clue to its mode of action in that it suggests that
peretinoin may prevent the occurrence of new liver tumours. These
results reinforce the analysis in the phase II/III study suggesting
that peretinoin suppresses HCC recurrence.

*Child-Pugh scoring system, which corresponds to A, B or C,
classifies hepatic impairment in patients with liver cirrhosis and
is used to assess the prognosis of the patients.

About the subgroup analyses of the Phase II/III trial

In these subgroup analyses, Child-Pugh A patients, who have
relatively preserved liver function, were selected to evaluate the
efficacy (recurrence free survival rate; RFS) of peretinoin. The
evaluation of the efficacy endpoints for HCC or HCC related disease
(including overall survival and RFS) can be confounded by the
inclusion of patients with moderate or severe (Child-Pugh B or C)
hepatic impairment because these patients have higher rates of
adverse events, including death, due to the underlying hepatic
cirrhosis. Recurrence of HCC is generally divided into two types:
intrahepetic metastasis and de novo (multicentric)
carcinogenesis. Almost all recurrences occurring among patients who
have had treatment for a major tumor with a diameter less than 20mm
are due to de novo carcinogenesis, so patients with a
previous tumor diameter of less than 20 mm were selected to assess
the effect of peretinoin on de novo carcinogenesis.

Among the 401 patients in the Phase II/III trial, 310 patients
had Child-Pugh A liver impairment, and 144 patients had Child-Pugh
A liver impairment and a previous major tumor with a diameter less
than 20mm. In the Child-Pugh A subgroup, peretinoin 600mg/day
(n=100) reduced the risk of HCC recurrence or death approximately
40% compared to placebo (n=106) [HR=0.60 (95% CI: 0.40-0.89)]. In
the subgroup with Child-Pugh A and previous major tumor size less
than 20 mm, peretinoin 600 mg/day (n=49) showed a 62% reduction in
the risk of HCC recurrence and death compared to placebo (n=49)
[HR=0.38 (95% CI: 0.20-0.71)].

Adverse events considered related to peretinoin were mainly
albuminuria, hypertension, and headache, but all of these were
tolerable.

The subgroup analyses in patients with Child-Pugh A hepatic
impairment showed a clearer suppressive effect on HCC recurrence
than in the phase II/III trial, which was greater in the subgroup
of patients who had previous had a major tumor with a diameter less
than 20mm. It is considered that the efficacy may be due to the
suppression de novo carcinogenesis.

These results reinforced the suppressive effect of peretinoin on
HCC recurrence suggested by the phase II/III study.

About the phase II/III trial

This trial evaluated the ability of peretinoin to suppress the
recurrence of HCC in patients who had undergone curative therapy
for hepatitis C virus (HCV) positive HCC. These results were also
presented at ASCO 2010 held in Chicago, USA, in June 2010 and ILCA
2010 held in Montreal, Canada, in September 2010.

The results of the Phase II/III trial indicated that peretinoin
600 mg/day given daily for up to 96 weeks reduced the recurrence of
HCC after curative therapy when compared to placebo.

Expert comments on this trial

Dr. Kiwamu Okita (superintendent at Shimonoseki Kohsei Hospital,
and professor emeritus at Yamaguchi University), the chairperson of
the coordinating committee for the Phase II/III trial, said, "In
these subgroup analyses of our trial, we could see clearer effect
of peretinoin and it supports our Phase II/III clinical trial data.
And we strongly suggest that peretinoin suppress de novo
carcinogenesis of HCC. Considering with this, we suppose that
peretinoin can suppress not only HCC recurrence but also
carcinogenesis from cirrhosis."

About Peretinoin

Peretinoin is an oral acyclic retinoid with a vitamin A-like
structure, and its main targeting molecule is the retinoid nuclear
receptor.

About Kowa

Kowa Company, Ltd. (Headquarters: Nagoya, Japan , President
& CEO: Yoshihiro Miwa, "Kowa") is a privately held
multinational company headquartered in Nagoya, Japan. Established
in 1894, Kowa is actively engaged in various manufacturing and
commercial activities in the fields of pharmaceutical, life
science, information technology, textiles, machinery and various
consumer products. In its ethical pharmaceutical business section,
the company offers the hypercholesterolemia drug Livalo
(pitavastatin), among other products, to the Japanese, US and other
markets worldwide, and is in the process of global expansion of
Livalo.

Kowa's US subsidiaries include Kowa Research Institute, Inc.,
for the research and development of pharmaceutical products, and
Kowa Pharmaceuticals America, Inc., which markets their
pharmaceutical products. European subsidiaries include Kowa
Research Europe, Ltd., for the research and development of
pharmaceutical products, and Kowa Pharmaceutical Europe Co. Ltd.,
which markets their pharmaceutical products. Kowa is organizing its
global network from Japan-Europe-US trilateral bases.

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